Topoisomerases I and II are nuclear enzymes that are involved in DNA replication and are targets for anticancer therapy. Clinically useful antitumor drugs such as camptothecin, irinotecan and topotecan interfere with the function of topoisomerase I (Top I). Antitumor drugs, such as doxorubicin, daunorubicin, etoposide, teniposide, amrubicin and amsacrine, inhibit topoisomerase II (Top II). Numerous efforts have focused on identifying efficacious and safe combination therapies of Top I and II inhibitors. These efforts are attributed to the collateral drug sensitivity of the enzymes. Top I inhibitor exposed cancer cells compensate the obstruction of DNA replication by enhancing Top II activity. This effect further sensitizes cancer cells to Top II inhibitors (Sugimoto, et al., Cancer Res, 1990. 50(24): 7962-5).
Some combination therapies of topoisomerase I and II inhibitors have been shown to inhibit cancer cell growth in vitro. However, clinical studies of these combinations have not progressed beyond phase II trials for several reasons. For example, doxorubicin provided a >20% overall response rate in patients with small cell lung cancer (Grant, et al., J Clin Oncol, 1992. 10(3): 484-98). However, when doxorubicin was administered with irinotecan, the combination showed no improvement in efficacy, providing only a 12.9% overall response in patients (Xenidis, et al., Cancer Chemother Pharmacol, 2011. 68(1): 63-8). The combination of amrubicin and irinotecan improved overall response up to 67% but elicited severe hematological toxicity in 71% of patients (Harada, et al., Jpn J Clin Oncol, 2014. 44(2): 127-33). Further, a clinical trial of topotecan and pegylated liposomal doxorubicin was terminated due to dose-limiting toxicity and the inability to arrive at a tolerable combination dose (Ryan, et al., Am J Clin Oncol, 2000. 23(3): 297-300). The results of clinical combinations of Top I and II inhibitors typically fall within one of two categories: little to no improvement in therapeutic efficacy; or augmented toxicity compared to the single drug counterparts.
Polymer-drug conjugates have been explored for the administration of single chemotherapy agents and can have clinical benefits over the drug administered alone (Duncan, Adv Drug Deliv Rev, 2009. 61(13): 1131-48). Clinical benefits may include reduced liver accumulation, enhanced drug localization in tumors, and improved pharmacokinetics (Vasey, et al., Clin Cancer Res, 1999. 5(1): 83-94). Conjugation of an anticancer drug to a polymer can improve clinical efficacy by promoting drug accumulation in tumors rather than in organs via the enhanced permeation and retention effect (Lammers, et al., J Control Release, 2005. 110(1): 103-18). This method ensures that tumors are exposed to effective amounts of the drug combination.
While some drug conjugates have been prepared and evaluated, they need further improvements to yield superior efficacies (R. Duncan, Adv Drug Delivery Revs vol. 61, 2009). Thus, there exists the need for anticancer therapies that are effective in treating cancer with reduced side effects.
It is an object of the invention to provide improved pharmaceutical compositions for delivering two or more therapeutic agents to a patient in need of treatment, and particularly, for reducing or preventing tumor growth in a cancer patient while limiting toxicity from the active agent.
It is yet another object of the invention to provide improved methods of treating cancer in a patient, and more particularly to reduce or prevent tumor growth in a cancer patient with reduced side effects from the same drugs typically delivered alone.
It is another object of the invention to provide improved pharmaceutical compositions for delivering to a patient two or more therapeutically active agents.
It is yet another object of the invention to provide methods for making these compositions.